It is now well established that human papillomavirus (HPV) is the cause of cervical cancer and other HPV-associated malignancies such as anogenital (anus, vulvar, vaginal and penile) cancers and a subset of head and neck cancers. In particular, HPV16 and HPV 18 are responsible for about 70% of all cervical cancers worldwide.
To date, two prophylactic HPV vaccines are on the market (Gardasil and Cervarix). The aim of the prophylactic vaccines is to induce humoral immune responses by stimulating the production of neutralizing antibodies specific for the HPV viral capsid proteins, L1 and L2. Although the preventive vaccines are an important milestone for the control of HPV induced cervical cancer and possibly other HPV-associated malignancies, the effect of these vaccines will not be significantly observed for 20-40 years (Ma B et al., Current Cancer Therapy Reviews, 2010). Moreover, since the coverage of mass vaccination for the prophylactic vaccines are to date limited in addition to a substantial population worldwide that already are HPV infected, HPV-associated malignancies will continue to progress. Thus, it will be important to develop HPV-specific therapeutic vaccines in order to reduce the mortality and morbidity of HPV-associated malignancies and its precursor lesions (Ma B et al., Current Cancer Therapy Reviews, 2010).
The development of various cancer vaccines and cancer immunotherapy strategies has throughout the last two decades expanded. Still, only one therapeutic cancer vaccine, called Provenge (Dendreon INC) has so far been approved to be applied as standard therapy for prostate cancer. Notably, due to ethical reasons the majority of therapeutic cancer vaccines are tested on a patient group bearing a late stage tumor. This patient group is substantially immunosuppressed meaning that the tumor cells have for long escaped the immune system and contributed to induce immunological tolerance to the tumor along carcinogenesis. In addition, the choice of antigens (tumor-specific vs. tumor-associated) applied as vaccines are critical in order to induce tumor-specific immune responses and avoid killing of healthy cells in the patients which may lead to serious adverse events. Thus, the major challenges in cancer immunotherapy are to break the immunological tolerance and activate tumor-specific effector functions to recognize and kill tumor cells. Although some case reports show clinical response to therapeutic cancer vaccines in late stage tumor patients, the most common primary endpoint is to observe the impact on overall survival compared to conventional therapy (surgery, chemo and radiation therapy). However, most studies are either not conclusive or that they completely fail to show this. One reason for the negative results lies in the patient group carrying end-stage tumors that are challenging to treat in the first place. A possible strategy could be to include patients with early-stage tumors in therapeutic vaccine trials.
One strategy is to target pre-cancerous lesions. The challenges for this strategy are mainly the lack of reliable biomarkers that are specifically expressed by precancerous lesions for many tissues and poor medical screening (either non-existing or that the existing method suffers from lack of sensitivity). Exceptionally, this is not the case for HPV-induced malignancies. For instance, the majority of western countries have good screening programs for cervical dysplasia and cervical cancer by performing the papanicolaou test (Pap smear test). If there are unclear or abnormal results from Pap smear test, colposcopy will be performed (National Cervical Cancer Coalition). HPV-testing may also be recommended for some patients to detect the presence of “high-risk” HPV-type in the precancerous lesion. Thus, HPV represents a potential biomarker for HPV-associated precancerous lesions, in particular cervical intraepithelial dysplasia (CIN).
DNA vaccines have shown increasing promise for the treatment of human diseases, in particular cancer. DNA vaccines induce strong antigen-specific immune responses and can be repeatedly administered to maintain the target-specific immune responses. Such vaccines are considered to be safe and simple and cheap to produce on a large scale compared to other cancer therapeutic formats. Numerous immunotherapeutic interventions fail to induce immunological memory. Exceptionally, DNA vaccination ensures sustained release of the vaccine product in vivo which enhances antigen-specific immunological memory. Direct delivery of antigens to professional antigen-presenting cells (APCs) stimulates both CD4+ and CD8+ T cell immune responses in vivo. Such strong cellular immune responses have been demonstrated to specifically recognize and kill antigen-positive malignant cells efficiently both in vitro and in vivo.
There is still a need in the art for improved vaccines for inducing strong and specific immune responses against HPV responsible for both infectious diseases and cancers.